Novel BCL11B truncation variant in a patient with developmental delay, distinctive features, and early craniosynostosis

Eto, Kaoru; Machida, Osamu; Yanagishita, Tomoe; Yamamoto, Kiyomi; Chiba, Kentaro; Aihara, Yasuo; Hasegawa, Yukiko; Nagata, Masanobu; Ishihara, Yasuki; Miyashita, Yohei; Asano, Yoshihiro; Nagata, Satoru; Yamamoto, Toshiyuki

doi:10.1038/s41439-022-00220-x

Cited by 11 publications

(7 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The transcription factor Bcl11b has been linked to neurodevelopmental (Lessel et al, 2018), neurodegenerative (Kunkle et al, 2016; Song et al, 2022) and neuropsychiatric disorders (Whitton et al, 2018; Whitton et al, 2016). BCL11B mutations in humans are associated with neurodevelopmental delay, overall learning deficits as well as impaired speech acquisition and autistic features (Eto et al, 2022; Lessel et al, 2018; Punwani et al, 2016; Yang et al, 2020). Moreover, conditional ablation of Bcl11b selectively in the adult murine hippocampus results in impaired learning and memory behavior (Simon et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Bcl11b (also known as Ctip2) is a zinc finger transcription factor that has been implicated in various disorders of the nervous system including Alzheimer’s and Huntington’s disease, and schizophrenia (Kunkle et al, 2016; Song et al, 2022; Whitton et al, 2018; Whitton et al, 2016). Patients with BCL11B mutations present with neurodevelopmental delay, overall learning deficits as well as impaired speech acquisition and autistic features (Eto et al, 2022; Lessel et al, 2018; Punwani et al, 2016; Yang et al, 2020). Bcl11b is expressed in several neuron types, including the dentate gyrus granule neurons (DGN) of the hippocampus.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

Britsch

Koumoundourou

Rannap

et al. 2023

Preprint

View full text Add to dashboard Cite

The transcription factor Bcl11b has been linked to neurodevelopmental and neuropsychiatric disorders associated with synaptic dysfunction. Bcl11b is highly expressed in dentate gyrus granule neurons and is required for the structural and functional integrity of mossy fiber-CA3 synapses. The underlying molecular mechanisms, however, remained unclear. We show that the synaptic organizer molecule C1ql2 is a direct functional target of Bcl11b that regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapses in vivo and in vitro. Furthermore, we demonstrate C1ql2 to exert its functions through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). Interruption of C1ql2-Nrxn3(25b+) interaction by expression of a non-binding C1ql2 mutant or by deletion of Nrxn3 in the dentate gyrus granule neurons recapitulates major parts of the Bcl11b as well as C1ql2 mutant phenotype, and interferes with C1ql2 targeting to the synapse. Together, this study identifies a novel C1ql2-Nrxn3(25b+)-dependent signaling pathway through which Bcl11b controls mossy fiber-CA3 synapse function. Thus, our findings contribute to the mechanistic understanding of neurodevelopmental disorders accompanied by synaptic dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

Britsch

Koumoundourou

Rannap

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Beyond that, the brain MRI revealed callosal agenesis, hippocampal malformations, parallel Although hematopoietic stem-cell transplantation was successful in treating the SCID, the patient later developed ID with spastic quadriplegia and seizures, which are welldescribed features of NDDs. To date, 16 additional articles have been published, covering a total number of 57 individuals with variations in the BCL11B gene loci [14,[63][64][65][66][67][68][69][70][71][72][73][74][75][76][77]. The reported genetic variants and clinical symptoms make a systematic genetic/phenotypic correlation of the BCL11B gene more feasible.…”

Section: Bcl11b-related Nddsmentioning

confidence: 99%

“…Symptoms and their prevalence in patients with variations in BCL11B. Data condensed from[13,[62][63][64][65][66][67][68][69][70][71][72][73][74][75][76].…”

mentioning

confidence: 99%

The Role of Bcl11 Transcription Factors in Neurodevelopmental Disorders

Seigfried,

Britsch

2024

Biology

View full text Add to dashboard Cite

Neurodevelopmental disorders (NDDs) comprise a diverse group of diseases, including developmental delay, autism spectrum disorder (ASD), intellectual disability (ID), and attention-deficit/hyperactivity disorder (ADHD). NDDs are caused by aberrant brain development due to genetic and environmental factors. To establish specific and curative therapeutic approaches, it is indispensable to gain precise mechanistic insight into the cellular and molecular pathogenesis of NDDs. Mutations of BCL11A and BCL11B, two closely related, ultra-conserved zinc-finger transcription factors, were recently reported to be associated with NDDs, including developmental delay, ASD, and ID, as well as morphogenic defects such as cerebellar hypoplasia. In mice, Bcl11 transcription factors are well known to orchestrate various cellular processes during brain development, for example, neural progenitor cell proliferation, neuronal migration, and the differentiation as well as integration of neurons into functional circuits. Developmental defects observed in both, mice and humans display striking similarities, suggesting Bcl11 knockout mice provide excellent models for analyzing human disease. This review offers a comprehensive overview of the cellular and molecular functions of Bcl11a and b and links experimental research to the corresponding NDDs observed in humans. Moreover, it outlines trajectories for future translational research that may help to better understand the molecular basis of Bcl11-dependent NDDs as well as to conceive disease-specific therapeutic approaches.

show abstract

“…Studying the function of BCL11b by knocking out the gene is challenging (Longabaugh et al, 2017). Mice that lack the two alleles of BCL11b die shortly after birth, exhibiting defects in multiple tissues, including the immune system, central nervous system (CNS), skin, thymus, among other organs (Eto et al, 2022; Kominami, 2012; Przybylski et al, 2022; Simon et al, 2020), which suggests the importance of BCL11b during development. For example, in brain, BCL11b serves as a marker of layer V subcerebral projection neurons and striatal interneurons (Lennon et al, 2017, 2016; Simon et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

BCL11b interacts with RNA and proteins involved in RNA processing and developmental diseases

Sobhy

Aït-Ammar

et al. 2020

Preprint

View full text Add to dashboard Cite

Although BCL11b (B-cell lymphoma/leukemia 11B, CTIP2) is a well-known transcription repressor and tumor suppressor, its functions and cellular pathways are largely unknown. Here, we show that BCL11b interacts with RNA splicing/processing and nonsense-mediated decay (NMD) proteins, including FUS, SMN1, UPF1 and Drosha. Mass spectrometry analysis (LC-MS/MS) shows that BCL11b interacts with histones, polymerases, and chromatin remodeling (CHD, SWI/SNF, and topoisomerase) proteins. BCL11b-bound RNAs were UV cross-linked and sequenced (CLIP-seq) showing that BCL11b binds to coding and noncoding RNAs (ncRNAs). Surprisingly, RNA transcripts and proteins produced by the same genes like FUS, ESWR1, CHD and Tubulin, were found bound to BCL11b. Deeper analysis of the CLIP-seq data further suggested that BCL11b binds to nonsense mediated RNA decay and retained introns transcripts. Our study is the first genome-wide study of BCL11b-protein and BCL11b-RNA interactants. Our results suggest that the functions of BCL11b are not restricted to the regulation of gene transcription. BCL11b may also control physiologic and physiopathologic pathways by direct bindings to protein complexes, coding RNA and non-coding RNA.

show abstract

Novel BCL11B truncation variant in a patient with developmental delay, distinctive features, and early craniosynostosis

Cited by 11 publications

References 25 publications

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

The Role of Bcl11 Transcription Factors in Neurodevelopmental Disorders

BCL11b interacts with RNA and proteins involved in RNA processing and developmental diseases

Contact Info

Product

Resources

About